title: LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1.
abstract: The LIM homeobox 2 transcription factor Lhx2 is known to control crucial aspects of neural development in various species. However, its function in human neural development is still elusive. Here, we demonstrate that LHX2 plays a critical role in human neural differentiation, using human embryonic stem cells (hESCs) as a model. In hESC-derived neural progenitors (hESC-NPs), LHX2 was found to be expressed before PAX6, and co-expressed with early neural markers. Conditional ectopic expression of LHX2 promoted neural differentiation, whereas disruption of LHX2 expression in hESCs significantly impaired neural differentiation. Furthermore, we have demonstrated that LHX2 regulates neural differentiation at two levels: first, it promotes expression of PAX6 by binding to its active enhancers, and second, it attenuates BMP and WNT signaling by promoting expression of the BMP and WNT antagonist Cerberus 1 gene (CER1), to inhibit non-neural differentiation. These findings indicate that LHX2 regulates the transcription of downstream intrinsic and extrinsic molecules that are essential for early neural differentiation in human.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan, Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100, Taiwan and Graduate Institute of Clinical Genomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Hou
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chuang
authors.forename: Cheng-Fu
authors.initials: CF
authors.lastname: Kao
authors.forename: Shen-Ju
authors.initials: SJ
authors.lastname: Chou
authors.forename: Lee
authors.initials: L
authors.lastname: Stone
authors.forename: Hong-Nerng
authors.initials: HN
authors.lastname: Ho
authors.forename: Chung-Liang
authors.initials: CL
authors.lastname: Chien
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Kuo
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C514249:CER1 protein, human; D016207:Cytokines; D005136:Eye Proteins; D018398:Homeodomain Proteins; C489783:LHX2 protein, human; D060850:LIM-Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors